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Journal of Medical Ultrasonics

https://doi.org/10.1007/s10396-020-01030-w

SPECIAL FEATURE: REVIEW ARTICLE

Everything you need to know about ultrasound for diagnosis of gallbladder diseases

Role of endoscopic ultrasound for gallbladder disease


Kazunari Tanaka1 · Akio Katanuma1 · Tsuyoshi Hayashi1 · Toshifumi Kin1 · Kuniyuki Takahashi1

Received: 10 February 2020 / Accepted: 18 May 2020


© The Author(s) 2020

Abstract
Endoscopic ultrasonography (EUS) has excellent spatial resolution and allows more detailed examination than abdominal
ultrasonography (US) in terms of qualitative diagnosis of tumors and evaluation of tumor invasion depth. To understand the
role of EUS in gallbladder disease, we need to understand the normal gallbladder wall structure and how to visualize it on
EUS. In addition, gallbladder lesions can be classified into two broad categories: protuberant and wall-thickening lesions.
Here, the features on EUS were outlined. We also outlined the current status of EUS-FNA for gallbladder lesions as there
have been scattered reports of EUS-FNA in recent years.

Keywords EUS · EUS-FNA · Gallbladder polyp · Gallbladder carcinoma

Introduction Herein, we describe the current applications of EUS-FNA


for gallbladder lesions.
Ultrasonography (US) is widely performed as a screening
test for gallbladder lesions as it is less invasive and can be 1. Normal anatomy of the gallbladder wall
done easily. Computed tomography (CT) or magnetic reso-
nance imaging (MRI) is often used for further evaluation In US, the gallbladder wall is visualized as two layers, a
when clinical questions persist after US has been performed. hypoechoic inner layer and a hyperechoic outer layer, which
CT is suboptimal for spatial resolution and hence limited correspond to the mucosa through the shallow and deep sub-
in its ability to provide differential diagnosis of gallbladder serosal layers, respectively [1] (Fig. 1). Normally, the gall-
lesions. However, it is useful for diagnosis of the presence bladder wall is at most 3 mm thick with a smooth luminal
of certain large gallbladder lesions and their progression. In surface. A gallbladder wall measuring ≥ 4 mm is considered
cases where malignancy is suspected based on other tests, to be thickened.
a qualitative diagnosis by MRI is useful. It is also possible
to understand the overall picture of the disease by magnetic 2. Methods for visualization of gallbladder lesions
resonance cholangiopancreatography. EUS has a high spatial by EUS
resolution and allows for a more detailed examination of the
gallbladder because it can approach and examine the organ There are two types of EUS scopes, radial scanning and
at a closer range than US. This makes it possible to make convex array. These devices provide different images and
a qualitative diagnosis of lesions and evaluate tumor inva- are therefore used in various visualization methods. Kaneko
sion depth with EUS. There have also been recent studies et al. [2] performed a prospective comparative study on the
on EUS fine-needle aspiration (FNA) in gallbladder disease. differences in visualization between these two devices in the
Thus, EUS-FNA may potentially augment difficulties in the examination of the pancreaticobiliary region.
pathological examination of gallbladder lesions. With regard to gallbladder long-axis visualizing capabil-
ity, convex array EUS was inferior to radial scanning EUS.
However, there was no significant difference in the lesion
* Kazunari Tanaka
kazunari0511@gmail.com imaging and new lesion imaging between the two groups.
Hence, in settings where both devices are available for use,
1
Center for Gastroenterology, Teine Keijinkai Hospital, the features of each device should be clearly understood, and
1‑40‑1‑12 Maeda, Teine‑ku, Sapporo 006‑8555, Japan

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Journal of Medical Ultrasonics

i) Radial scan type

For a gastric scan, after observing the pancreas, advance the


scope into the descending duodenum and stretch the scope
into the short scope position. Inflate the balloon slightly,
identify the bile ducts, withdraw while rotating counter-
clockwise, and identify the cystic duct junction. Inflate the
balloon further, withdraw the scope, and examine from the
cystic duct to the neck of the gallbladder (Fig. 2a). Depend-
ing on the patient, it may be possible to examine the whole
gallbladder, including the fundus (Fig. 2b). In cases where
the whole gallbladder cannot be examined in the short scope
position, in the duodenal bulb, press the scope tip against the
superior duodenal flexure, tilt the scope upward, and lightly
Fig. 1  Normal gallbladder. The gallbladder wall is divided into an advance it assuming a long scope position (Fig. 3a). Clock-
inner low echoic layer and an outer high echoic layer wise rotation causes the scope to advance in the direction
of the descending duodenum (Fig. 3b). Visualize the cystic
duct junction, and successively examine the cystic duct and
proper use should be implemented according to the patient’s the neck, body, and fundus of the gallbladder (Fig. 3c). Dur-
medical condition. ing this procedure, the short scope position and gallbladder
To minimize oversight in testing, confirmation using direction are opposite. In transgastric scanning, observation
different modalities such as magnetic resonance cholangio- may be possible by either withdrawing the scope with the
pancreatography is important before EUS. As the gallblad- balloon inflated from the short scope position or pressing the
der structure and position vary from patient to patient, the scope against the pyloric ring with the balloon inflated and
gallbladder curvature and the positions of lesions should assuming the long scope position.
be verified in advance, preventing oversight during EUS.
The position of the gallbladder fundus, in particular, var- ii) Convex array
ies largely between individuals, and caution is necessary as
failure to ascertain the overall gallbladder structure before When examining the gallbladder by transgastric scanning,
performing the examination may result in lesion oversight it is easier to identify the bile ducts using the portal vein as
and inability to obtain accurate observations. the starting point. By following the intrahepatic portal vein
The key points for gallbladder examinations for each type of the left lobe of the liver and identifying the hilar portal
of EUS are presented below. vein, the hilar hepatic ducts can be visualized in the deep
part of the portal vein (Fig. 4a).

Fig. 2  Radial scan type (short-


scope position). a Short-scope
position. b EUS image of the
gallbladder in the short-scope a b
position

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Fig. 3  Radial scan type (long-


scope position). a Long-scope
position in the duodenum bulb. a b c
b Clockwise rotation causes
the scope to advance in the
direction of the descending
duodenum

Accordingly, visualization of the cystic duct junction is it is important to make a thorough observation including
occasionally possible by continuing to advance the scope, the gallbladder fundus by visualizing successively from the
and visualization from the cystic duct to the gallbladder cystic duct toward the gallbladder neck.
neck is occasionally possible by rotating the scope (Fig. 4b).
However, as the direction of rotation at this point varies with iii) Contrast‑enhanced harmonic EUS
each patient, visualization should be performed while care-
fully following the cystic duct (Fig. 4c). Note that examina- Although contrast-enhanced harmonic EUS for gallbladder
tion of the entire gallbladder from within the stomach is not disease is not covered by health insurance, Choi et al. [3]
always possible. have reported that the presence of irregular intratumoral
In duodenal bulb scanning, the hilar hepatic ducts are vessels and a perfusion defect on contrast EUS can diag-
identified by visualizing the portal vein and tilting the scope nose gallbladder cancer in gallbladder polyps measuring at
downward while withdrawing it in counterclockwise rotation least 10 mm with a sensitivity and specificity of 93.5 and
(Fig. 5a). The cystic duct junction can be recognized through 93.2%, respectively (Fig. 6). Imazu et al. [4] also reported
this process (Fig. 5b). By rotating the scope while following that inhomogeneously enhanced patterns were observed in
the cystic duct, it is possible to visualize the whole gallblad- contrast EUS. However, further accumulation of knowledge
der from the neck to the fundus (Fig. 5c). As the direction is desired as there has been apparently no large-scale study
of rotation at this point also varies from patient to patient,

Fig. 4  Convex array (transgas-


tric scanning). a EUS image of
the cystic duct junction. b EUS
image of the gallbladder neck a
and body. Gn: neck of gallblad-
der, Gb: body of gallbladder

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Fig. 5  Convex arrayed (duo-


denal bulb scanning). a EUS b
image of the cystic duct and
gallbladder neck and body. a
b Fundus of gallbladder. Gf:
fundus of gallbladder

Fig. 6  Contrast EUS for


gallbladder carcinoma. a
Conventional EUS demonstrates
a hypoechoic mass in the gall-
bladder. b Contrast-enhanced
harmonic EUS indicates that
the area has perfusion defects
(arrow)

on contrast-enhanced harmonic EUS in gallbladder diseases significance of treating lesions collectively as gallbladder
to date. polyps before a definitive diagnosis lies in the early detec-
tion of malignant disease from these lesions. Therefore,
3. Differential diagnosis of gallbladder lesions protuberant gallbladder lesions are first divided into neo-
plastic and non-neoplastic lesions. Differential diagnoses
Gallbladder lesions are broadly divided into protuber- such as adenomas or carcinomas for neoplastic lesions and
ant and wall-thickening lesions. Protuberant lesion is an cholesterol polyps, hyperplastic polyps, and gallbladder
inclusive category encompassing a variety of diseases, adenomyomatosis for non-neoplastic lesions are based on
both epithelial and non-epithelial, as well as benign and size, pedunculation, morphology, surface characteristics,
malignant diseases. It is a generic term for lesions that and internal echo. On the other hand, wall-thickening
have the specific morphological feature of forming a pro- lesions denote lesions in which the gallbladder wall is dif-
tuberance localized to the luminal side of the gallbladder fusely thickened. Differential diagnosis is made with ref-
[5]. In differentiating protuberant gallbladder lesions, the erence to the extent of wall thickening, surface structure,
classification of benign protuberant lesions by Christensen and presence or absence of Rokitansky–Aschoff sinuses
et al. is used [6]. However, from a clinical perspective, the (RAS).

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Ultrasonographic features of gallbladder protuberant punctiform foci reflecting cholesterolosis are visible [14]
lesions and gallbladder wall-thickening lesions are summa- (Fig. 7). Peduncles are thin and frequently unobserved even
rized in Tables. 1 and 2, respectively. on EUS.
When polyps reach ≥ 10 mm, epithelial hyperplas-
4. Protuberant lesions tic changes are reflected as lobulation, and internal echo
decreases, making differentiation from adenoma and early
i) Non‑neoplastic lesions (gallbladder polyps) gallbladder cancer difficult in some cases and necessitating
caution (Fig. 8).
Gallbladder polyps are small, localized, raised lesions B. Hyperplastic polyps: Hyperplastic polyps are classified
observed on the mucosal surface of the gallbladder. Histo- as proper epithelial or metaplastic epithelial polyps, and they
pathologically diverse diseases are included, whether benign frequently multiply. The proper epithelial type occurs sin-
or malignant, neoplastic or non-neoplastic, and epithelial gly, measures ≥ 10 mm, is papillated to lobulated, and shows
or non-epithelial. In daily clinical practice, benign lesions relative internal uniformity. If accompanied by cholesterolo-
measuring < 2 cm are usually detected [7]. Most gallbladder sis, internal punctiform echogenic foci are observed, which
polyps are asymptomatic and discovered incidentally during complicates differentiation from cholesterol polyps (Fig. 9).
medical or comprehensive health examinations. The preva- C. Inflammatory, fibrous, and granulomatous polyps:
lence rate is reported to be within 4.2–9.5% in East Asia Whether to treat inflammatory, fibrous, and granulomatous
[8–11] and 3–7% in Western countries [12]. polyps as distinct or similar remains controversial. Inflam-
The main types of gallbladder polyp are as follows: matory polyps are relatively rare, comprising 1.4–12% of
A. Cholesterol polyps: These are the most common gallbladder polyps [15–18]. These polyps, which result from
gallbladder polyps and comprise 62.8% of all gallbladder hyperplasia of edematous loose connective tissues, are inter-
polyps. Although multiple polyps measuring ≤ 10 mm are nally hypoechoic and occasionally accompanied by inflam-
highly likely to be cholesterol polyps, [5] caution is nec- matory thickening of the gallbladder wall.
essary as 5% of polyps are cancerous even if they meas- The characteristic EUS findings are internal anechoic
ure ≤ 10 mm [13]. The characteristic findings on EUS are a spots with hyperechoic polyp surface borders. These find-
deeply notched granular surface and morular morphology. ings appear to occur because of the difference in the acoustic
The internal echo is rough or granular, and highly echogenic features between the single surface layer of the columnar

Table 1  Ultrasonographic Form Surface Internal echo


features of gallbladder
protuberant lesions Cholesterol polyp ・Morular or oval ・Granular ・Rough or granular
・Highly echogenic punctiform foci
Hyperplastic polyp ・Papillated or lobulated ・Smooth ・Low echogenicity
・Uniform low echogenicity
Inflammatory polyp ・Ovla or lobulated ・Smooth ・Anechoic spots
Fibrous polyp ・Hyperechoic polyp ・Uniform low echogenicity
Granulomatous polyp surface border
Adenomyomatosis ・Sessile or oval ・Smooth ・Anechoic spots
・Comet tail artifact
・Uniform low echogenicity
Adenoma ・Oval ・Smooth or nodular ・Solid echogenicity
・Multiple microcystic spaces
Gallbladder carcinoma ・Oval or irregular ・Smooth or irregular ・Uniform internal echo
・Dense solid echo

Table 2.  Ultrasonographic Surface Internal echo


feature of gallbladder wall
thickened lesions Adenomyomatosis ・Smooth or irregular ・Cystic anechoic spots
・Comet tail artifacts
Xanthogranulomatous cholecystitis ・Smooth ・Mixed hyperechoic and
hypoechoic echotexture
Anomalous pancreaticobiliary junction ・Smooth ・Uniform low echogenicity
Gallbladder carcinoma ・Irregular or papillated ・Uneven hypoechogenicity

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Fig. 7  Cholesterol polyp. a This


polyp has a granular surface
and morular morphology.
The internal echo is rough or
granular. b Polypoid lesion with
non-neoplastic epithelium and
abundant stroma

Fig. 8  Cholesterol polyp resem-


bling early gallbladder carci-
noma. a EUS image of a solid
internal echogenicity polyp
without echogenic punctiform
foci. b (1, 2) Photomicrograph
demonstrating an aggregation of
foamy cells under the epithe-
lium

epithelium and the edematous stroma [19] (Fig. 10). Fibrous enlarged neoplastic glandular ducts observed as multiple
polyps are made up of connective tissue composed of fibro- microcystic spaces [20] (Fig. 12). Papillary adenomas are
blasts, fibrocytes, and collagen fibers, and imaging findings predominantly of the proper epithelial type with a low solid
resemble those of inflammatory polyps (Fig. 11). Granu- echo and must be differentiated from hyperplastic polyps.
lomatous polyps, which are formed from inflammatory Differentiation between adenomas and adenocarcinomas
granulation tissue, lack a surface epithelium and have a high based on imaging is considered difficult.
rate of comorbidity with acute cholecystitis and gallstones. B. Gallbladder carcinoma (protuberant type): Gall-
bladder carcinoma is considered in cases of diffuse or
ii) Neoplastic lesions localized irregular thickening of the gallbladder wall in
which an irregular mucous membrane surface and a loss
A. Adenomas: Adenomas are classified as tubular or pap- of uniformity in the inner hypoechoic layer are observed.
illary. Tubular adenomas, of which pyloric adenomas are Ultrasound imaging findings are classified as protuberant
common, are pedunculated to subpedunculated and oval. (peduncular/sessile), wall thickening, or both types. Of
The features on EUS are a relatively smooth or nodular the protuberant type, peduncular lesions (type Ip) often
surface, solid internal echogenicity, and the presence of

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Journal of Medical Ultrasonics

Fig. 9  Gallbladder hyperplastic


polyp. a EUS image of a pedun-
culated, lobulated, solid internal
echogenicity polyp. b (1, 2) The
polyp consists of duct glands
similar to the pyloric gland

Fig. 10  Gallbladder inflamma-


tory polyp. a EUS image show-
ing a pedunculated, smooth
surface polyp with an anechoic
area. b (1, 2) The stroma con-
sists of edematous and coarse
fibrous connective tissue. The
surface iconsists of simple
columnar epithelium

show morphological resemblance to adenomas (Fig. 13), 5. Wall‑thickening lesions


uniform internal echo, and dense solid echo. Adenocar-
cinomas are common among type Ip, whereas sessile i) Gallbladder adenomyomatosis
lesions (types Is and IIa) are frequently accompanied by
associated neighboring IIa and flat lesions. Because the Histopathologically, gallbladder adenomyomatosis is a
layered structure can be examined in detail by EUS, type disease that causes RAS and thickening of the gallbladder
Is lesions with a deep hypoechoic area or thinning of the wall owing to smooth muscle and fibrous tissue hyperplasia.
hyperechoic outer layer (Fig. 14) can be diagnosed as gall- Based on the location and morphology of the wall lesions,
bladder carcinoma with SS depth of invasion. However, gallbladder adenomyomatosis is classified as fundal (with a
in cases where the hyperechoic outer layer is retained, the focal lesion involving the gallbladder’s fundal region), seg-
depth of invasion may extend to the mucous membrane, mental (with thickening of the gallbladder neck or body), or
muscularis, or shallow SS layer, depending on the case, diffuse (with RAS hyperplasia and thickening that involve
and differentiation is difficult even by EUS. the whole gallbladder wall) (Fig. 15).
In gallbladder adenomyomatosis, the thickened wall has a
smooth surface but occasionally exhibits surface irregularity,
reflecting hyperplastic changes. A key point in its diagnosis

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Fig. 11  Gallbladder fibrous


polyp. a EUS image show-
ing a pedunculated, smooth
surface, uniformal echogenicity
hypoechoic polyp. b (1, 2) The
stroma consists of edematous
and coarse fibrous connective
tissue. The surface consists of
simple columnar epithelium

Fig. 12  Gallbladder adenoma.


a (1, 2) EUS image showing a
relatively smooth surface, solid
internal echogenicity polyp with
multiple microcystic spaces. b
Photomicrograph imaging of
the gallbladder adenoma

is to confirm the presence of cystic anechoic spots reflecting irregular thickening of the gallbladder wall and fibrosis.
RAS inside the thickened wall. Comet tail artifacts are also As the inflammation occasionally affects surrounding
occasionally observed owing to multipath reflection from organs such as the liver and transverse colon, differentia-
RAS or intramural calculi. tion from gallbladder carcinoma is frequently problematic.
The disease may result from impaction of stones in the
ii) Xanthogranulomatous cholecystitis neck of the gallbladder or biliary leakage into the gallblad-
der wall owing to RAS rupture or mucosal ulceration. In
Xanthogranulomatous cholecystitis is a unique form of cases without lithiasis, gallbladder carcinoma may be a
cholecystitis in which the gallbladder wall thickening possible cause. Differentiation between benign and malig-
primarily involves the SS layer and is accompanied by nant types based on EUS alone is frequently difficult.

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Fig. 13  Early gallbladder


carcinoma. a (1, 2) EUS image:
A homogenously hypoechoic
protruding lesion with a
granular surface is seen. The
outer layer of the gallbladder is
well preserved (arrow, retained
hyperechoic outer layer; arrow-
head, normal hyperechoic outer
layer). b Photomicrograph: A
pedunculated polypoid lesion
was diagnosed as well-differen-
tiated adenocarcinoma. It was
invading into but not through
the muscularis layer

Fig. 14  Advanced gallbladder


carcinoma. a EUS imaging of a
sessile elevated lesion with thin-
ning of the hyperechoic outer
layer (arrow, thinning of the
hyperechoic outer layer; arrow-
head, normal hyperechoic outer
layer). b (1, 2) Photomicro-
graph: Gallbladder carcinoma
with SS depth invasion

Fig. 15  Gallbladder adenomy-


omatosis. a Fundal type. b Dif- b
fuse type. c Segmental type
a

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iii) Hyperplasia of the gallbladder mucous membrane iv) Gallbladder carcinoma (wall‑thickening type)
accompanying anomalous pancreaticobiliary junction
In the wall-thickening type, differentiation from gallblad-
As an anomalous pancreaticobiliary junction leads to der adenomyomatosis and chronic cholecystitis is problem-
reflux of pancreatic juice into the biliary tract, hyperplas- atic, but in gallbladder carcinoma, the mucous membrane is
tic changes arise in the gallbladder mucous membrane irregular or papillated, thickened areas do not have uniform
(Fig. 16). Hyperplasia of the gallbladder mucous mem- thickness, and the layered structure is ill-defined. Further-
brane is recognized in 38–63% of patients with an anoma- more, microcysts and comet tail artifacts reflecting RAS are
lous pancreaticobiliary junction, with an even higher rate usually not observed (Fig. 17).
of 90–100% particularly in patients without bile duct dila-
tation [21, 22]. 6. EUS‑FNA for gallbladder lesions
In hyperplasia of the gallbladder mucous membrane,
epithelial height is increased, cellular proliferative activ- Bile duct biopsy is the first choice procedure in the patholog-
ity is accelerated, and a mechanism from hyperplasia to ical diagnosis of gallbladder lesions in which a biliary stric-
dysplasia and carcinoma is speculated. ture is present. However, when a biliary stricture is absent,
it is often necessary to rely on cytological examination of

Fig. 16  Hyperplasia of the


gallbladder mucous membrane
accompanying anomalous pan-
creaticobiliary junction. a EUS
image of the thickened inner
hypoechoic layer of the gall-
bladder. b Hyperplastic changes
in the gallbladder mucous
membrane. c ERCP image of
anomalous pancreaticobiliary
junction

Fig. 17  Gallbladder carcinoma


(wall-thickening type). a (1,
2) EUS image of irregular
gallbladder wall thickening
from the gallbladder body to
the fundus (arrow). b (1, 2)
Photomicrograph: Gallblad-
der carcinoma with SS depth
invasion

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Fig. 18  EUS-FNA for a


gallbladder lesions. a CT scan
shows a gallbladder lesion in
the gallbladder neck (arrow).
b EUS-guided FNA for a gall-
bladder mass lesion

bile collected from the gallbladder through the cystic duct, with the use and establishment of EUS-FNA for gallbladder
which makes diagnosis difficult. Cytological examination lesions.
using endoscopic naso-gallbladder drainage does not always
have a high success rate, requires a highly proficient practi- Acknowledgements We thank Dr. Edward Barroga (https​://orcid​
.org/0000-0002-8920-2607), Medical Editor and Professor of Aca-
tioner, and presents problematic points such as perforation demic Writing at St. Luke’s International University, for editing the
of the cystic duct when using a guidewire [23–25]. manuscript.
Although EUS-FNA is highly useful and widely used for
pancreatic carcinoma and gastrointestinal lesions, the deci- Compliance with ethical standards
sion to use EUS-FNA for biliary tract lesions, particularly
gallbladder carcinoma, should be made with care because of Conflict of interest The authors declare that there are no conflicts of
risks such as biliary fistula and dissemination to membranes. interest.
Regional lymphadenopathy is often noted in unresectable Ethical approval All procedures followed were in accordance with the
advanced gallbladder carcinoma [26]. Considering the risks ethical standards of the responsible committee on human experimenta-
such as invasive biliary fistula, which may affect neighbor- tion (institutional and national) and with the Helsinki Declaration of
ing organs including the liver, and peritoneal dissemination, 1964 and later versions.
aspiration from regional lymph nodes is preferable. Hijioka Informed consent Informed consent was obtained from all patients for
et al. have reported that FNA can be performed in gallblad- being included in the study.
der lesions without compromising diagnostic performance
or safety [26]. Moreover, the diagnostic performance of Open Access This article is licensed under a Creative Commons Attri-
EUS-FNA in gallbladder lesions is high, with a sensitivity, bution 4.0 International License, which permits use, sharing, adapta-
specificity, and diagnostic accuracy of 80–100%, 100%, and tion, distribution and reproduction in any medium or format, as long
83–100%, respectively [26–31]. as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
When directly puncturing the gallbladder wall, despite were made. The images or other third party material in this article are
the care taken to gain stroke distance by tangentially punc- included in the article’s Creative Commons licence, unless indicated
turing the gallbladder wall (Fig. 18), the wall may move otherwise in a credit line to the material. If material is not included in
if the gallbladder lumen remains and puncturing is often the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
difficult. In cases where lesions have invaded the liver, it is need to obtain permission directly from the copyright holder. To view a
recommended to puncture either the liver parenchyma as the copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/.
invasion site or the gallbladder wall that is in contact with
the liver parenchyma.

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